Hope on the Horizon

Blind people have a basic need to see.

Novel therapeutic approaches are sorely needed for people suffering from CEP290-based disease. Scientists around the world work tirelessly to develop safe and efficient therapies. Here is a brief overview of the most promising advancements.

Gene:CEP290:centrosomal protein 290
Variant type:Single nucleotide (intron) variant
Variant length:1 bp
Cytogenetic location:12q21.32
Genomic location:Chr12: 88101183 (on Assembly GRCh38)
Nucleotide change:2991+1655A-G
Functional consequence:cryptic splice donor activation
Preferred name:NM_025114.4(CEP290):c.2991+1655A>G
NCBI Reference Sequence:NM_025114.4
NCBI 1000 Genomes Browser:rs281865192
Condition Name:LCA10; MedGen: C1857821;

Initial strategies for the development of gene therapy for CEP290-associated LCA (LCA10) are under consideration. Although, the size of CEP290 disqualifies the use of AAV (packaging limit of 4.7kb) vector system for packaging the full-length gene, employing a lentivirus (packaging limit of 8-10kb) might be advantageous as it can accommodate the full-length CEP290 cDNA. Burnight and colleagues provided evidence that lentiviral vector expressing full-length human CEP290 can correct the CEP290 disease-specific cellular phenotype in patient-derived fibroblasts, but it is not certain whether the LV-mediated approach will be able to deliver to photoreceptors in patients (Burnight et al., 2014).

Another approach is miniCEP290. It was strategically designed to include CEP290’s membrane and microtubule-binding domains (Chapter 2; Drivas et al., 2013) and almost all of CEP290’s PCM-1, NPHP5, CC2D2A, and Rab8A binding domains (Chang et al., 2006; Gorden et al., 2008; Kim et al., 2008; Schäfer et al., 2008), while leaving out as much of CEP290’s known autoregulatory domains as possible (Chapter 2; Drivas et al., 2013) One group has reported the rescue of the retinal degeneration phenotype in an induced zebrafish model of CEP290 disease using just such a miniCEP290 (Baye et al., 2011). Subretinal injection of AAV particles carrying the cDNA expressing miniCEP290 580‐1180 into neonatal Cep290 rd16 mice resulted in significantly improved photoreceptor survival as compared to control injected mice (Zhang et al., 2017). Even though still too early to tell when miniCEP290 will make it into clinical testing, great work is being under investigation with patents of new compositions encoding fragment of CEP290 gene as reported by Drivas, Theodore G., and Bennett, Jean. In July 2019 IVERIC bio company announced a collaboration with UMass Medical School and Horae Gene Therapy Center and successful advancement of its minigene therapy program.

Stem cell therapies hold great promise for the future to restore lost retinal cells in complex disorders, including potentially LCA. However, transplantation of retinal cells, such as photoreceptors—which would be needed in LCA, remains at a preclinical stage (Kumaran et al., 2017).

Clinical trials have also been conducted to investigate the therapeutic potential of electronic retinal prostheses. Nonetheless, current epiretinal or subretinal devices cannot sufficiently substitute the high density of photoreceptors and they lead to very low levels of visual acuity (VA) improvement (Barry, et al., 2012)

An additional approach might be the use of CRISPR/Cas9-mediated gene editing where the editing takes place inside the human body; this is at present being developed by Editas/Allergan (Cambridge, MA). Allergan and Editas Medicine, Inc. announced also in July 2019 the Brilliance Phase 1/2 clinical trial of their experimental genome editing medicine open for patient enrollment. EDIT- 101 is to be administered via a subretinal (SRi) surgical technique.

A novel technique developed by David R. Liu, called Prime Editing (PE) is being farther developed and presented by Peter M.J. Quinn et al. as yet another potential IRD treatment. Prime editing is based on CRISPR technology, however unlike the traditional CRISPR which cuts both strands of the DNA, PE makes a single strand cut, the same reduces risks of off-target effect.

Another hopeful is an ongoing ILLUMINATE international clinical trial of sepofarsen. The purpose of the study is to confirm that sepofarsen improves eyesight (visual acuity) in patients with LCA10 due to the p.Cys998X pathogenic variant. Results for QR-110 targeting LCA 10 are sponsored by ProQR Company and led by research professors at Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania Artur V. Cideciyan, PhD and Samuel G. Jacobson MD, PhD. ProQR has started the first clinical trial in 2017 at academic hospitals in the US and Europe. The new treatment is built on a first-in-class investigational RNA-based oligonucleotide. The therapy is administered through intravitreal injections (IVTi) in the eye where the solution is given directly into the vitreous cavity without subretinal surgery. Participating patients showed improvement at three months after their first injection to the worse-seeing eye. Unfortunately, the study did not meet primary endpoint nor secondary endpoints at one year, resulting in no therapeutic benefit to the patients (as of 11. Feb. 2022). We are not giving up, and still hoping for more encouraging results once the technology will have been improved. Meanwhile, sincere thanks to ProQR and collaborating teams for their hard work, commitment and transparency.

More about clinical trials for this program can be found at Clinical Trials Register (2017-000813-22, Belgium – FPS Health-DGM) website or ClinicalTrials.gov (no. NCT03140969).

Is there any evidence from Genome-Wide Association Studies (GWAS) that established genetic, single-mutation-caused diseases are accompanied by other SNP correlations relevant to this disease? Is it feasible that the majority of SNP linkages found in non-coding regions of the genome also have an impact on single-mutation protein-coding regions? We’ve already witnessed they’re capable of. But to what extent is this true? How? What effect will this new piece of data have on the development of new therapies?

The way to understanding has yet to be found.


Burnight ER, Wiley LA, Drack AV, et al. CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype. Gene Ther 2014;21(7):662–672

Drivas T.G., (2013) Bridging the gap: defining the molecular mechanism of CEP290 disease pathogenesis, Chapter 2; Publicly Accessible Penn Dissertations. 851.

Chang, B., Khanna, H., Hawes, N., Jimeno, D., He, S., Lillo, C., Parapuram, S.K., Cheng, H., Scott, A., Hurd, R.E., et al. (2006). In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum. Mol. Genet. 15, 1847–1857.

Gorden, N.T., Arts, H.H., Parisi, M.A., Coene, K.L.M., Letteboer, S.J.F., van Beersum, S.E.C., Mans, D.A., Hikida, A., Eckert, M., Knutzen, D., et al. (2008). CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am. J. Hum. Genet. 83, 559–571.

Kim, J., Krishnaswami, S.R., and Gleeson, J.G. (2008). CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium. Hum. Mol. Genet. 17, 3796–3805.

Schäfer, T., Pütz, M., Lienkamp, S., Ganner, A., Bergbreiter, A., Ramachandran, H., Gieloff, V., Gerner, M., Mattonet, C., Czarnecki, P.G., et al. (2008). Genetic and physical interaction between the NPHP5 and NPHP6 gene products. Hum. Mol. Genet.17, 3655–3662.

Baye, L.M., Patrinostro, X., Swaminathan, S., Beck, J.S., Zhang, Y., Stone, E.M., Sheffield, V.C., and Slusarski, D.C. (2011). The N-terminal region of centrosomal protein 290 (CEP290) restores vision in a zebrafish model of human blindness. Hum. Mol. Genet. 20, 1467–1477.

Zhang, W., Li, L., Su, Q., Gao, G., Khanna, H., (2017). Gene therapy using a miniCEP290 fragment delays photoreceptor degeneration in a mouse model of Leber congenital amaurosis (LCA). Hum. Gene Ther., DOI: 10.1089/hum.2017.049

Drivas, Theodore G., and Bennett, Jean., (2018). Compositions and methods for treatment of disorders related to CEP290. United States Patent 10155794.

Kumaran, N., Moore, A.T., Weleber, R.G., Michaelides, M., (2017) Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. Br. J. Ophthalmol. 0:1–8.

Barry, M.P., Dagnelie, G. (2012) Argus II Study Group. Use of the Argus II retinal prosthesis to improve visual guidance of fine hand movements. Invest Ophthalmol Vis Sci. 53, 5095–101.

Bruna Lopes da Costa, Sarah R. Levi, Eric Eulau, Yi-Ting Tsai, and Peter M. J. Quinn., (2021) Prime Editing for Inherited Retinal Diseases, 10.3389/fgeed.2021.775330

Cideciyan, Artur V., Jacobson, Samuel G., Drack, Arlene V., Ho, Allen C., Charng, Jason, Garafalo, Alexandra V., Roman, Alejandro J., Sumaroka, Alexander, Han, Ian C., Hochstedler, Maria D., Pfeifer, Wanda L., Sohn, Elliott H., Taiel, Magali, Schwartz, Michael R., Biasutto, Patricia, Wit, Wilma de, Cheetham, Michael E., Adamson, Peter, Rodman, David M., Platenburg, Gerard, Tome, Maria D., Balikova, Irina, Nerinckx, Fanny, Zaeytijd, Julie De, Van Cauwenbergh, Caroline, Leroy, Bart P., Russell, Stephen R. (2018) Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nature Medicine. https://doi.org/10.1038/s41591-018-0295-0

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